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Towards generation of virus-free vaccines

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  • Full or part time
    Prof N J Stonehouse
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Despite the success of global mass vaccination programmes in dramatically reducing the world wide incidence of poliomyelitis, residual pockets of infection remain and the disease has yet to be eradicated. In order to eradicate this disease, there is a need for effective polio vaccines that do not rely on the cultivation of live virus for their manufacture. EV71 is a causative agent of hand, foot and mouth disease and a virus related to polio. It has been involved in several recent outbreaks that have resulted in fatalities. There is no current vaccine.
Virus-like particles (VLPs) are used in several vaccines e.g. against HPV and hepatitis B virus. However, for picornaviruses such as poliovirus and EV71, the production of VLPs is challenging because the processing of capsid proteins that is normally associated with RNA encapsidation and particle stability does not occur. This project will employ a combination of selection and structure-guided design to generate VLPs that are stable and maintain wild-type antigenicity.

Specific aims are:
Design mutations in both virus and VLPs.
Produce selected genetically stabilised VLPs by recombinant expression
Isolate recombinantly-expressed VLPs and assess their antigenic characteristics and thermal stability.

Funding Notes

The current projects involve a collaboration between Leeds (Nicola Stonehouse and Dave Rowlands), Reading, Oxford, NIBSC and The Pirbright insitute with funding from Gates/WHO and Sanofi Pasteur.

References

Selected References:

Forrest S., Lear Z., Herod M.R., Ryan M., Rowlands D.J. and Stonehouse N.J. (2014) Inhibition of the foot-and-mouth disease virus subgenomic replicon by RNA aptamers. Journal of General Virology. J. Gen. Virol. 95, 2649–2657

Tulloch F., Pathania U., Luke G.A., Nicholson J., Stonehouse N.J., Rowlands D.J., Jackson T., Tuthill T., Haas J., Lamond A. I, Ryan M.D. (2014) FMDV replicons encoding green fluorescent protein are replication competent. J. Virological Methods 209, 35–40

Panjwani A., Strauss M., Gold S., Wenham H., Jackson T., Chou J.J., Rowlands D.J., Stonehouse N.J., Hogle J.M., Tuthill T.J. (2014) Capsid protein VP4 of human rhinovirus induces membrane permeability by the formation of a size-selective multimeric pore. Plos Pathogens DOI: 10.1371/journal.ppat.1004294

De Colibus L., Wang X., Spyrou J.A.B., Kelly J., Ren J., Grimes J., Puerstinger G., Stonehouse N., Walter T.S., Hu Z., Wang J., Li X., Peng W., David J Rowlands D.J. ,Fry E.E., Rao Z & Stuart D.I.(2014) More-powerful virus inhibitors from structure-based analysis of HEV71 capsid-binding molecules. Nature Struc. Mol. Biol doi:10.1038/nsmb.2769

Shepherd D.A., Ariza A., Edwards T.A., Barr J.N, Stonehouse N.J.and Ashcroft A.E. (2014)
Probing Bunyavirus N protein oligomerisation using mass spectrometry. Rapid Commun. Mass Spectrom. 2014, 28, 793–800

Doble R., McDermott M.F., Cesur Ö., Stonehouse N.J#. and Wittmann M#. (2014) IL-17A RNA Aptamer: Possible Therapeutic Potential in Some Cells, More than We Bargained for in Others? Journal of Investigative Dermatology. 134, 852–855

Ren, J., Wang X., Hu, Z., Gao, Q., Sun, Y., Li, X., Porta, C., Walter, T.S., Gilbert,R.J., Zhao, Y., Axford, D., Williams, M., McAuley, K., Rowlands, D.J., Yin, W., Wang, J., Stuart, D.I., Rao, Z. & Fry, E.E. (2013) Picornavirus uncoating intermediate captured in atomic detail. Nature Com. DOI: 10.1038/ncomms2889

Wang X. Peng W., Ren J., Hu Z., Xu J., Lou Z., Li X., Yin W., Shen X., Porta C., Walter T.S., Evans G., Axford D., Owen R., Rowlands D.J., Wang J., Stuart D.I., Fry E.E. and Rao Z. (2011) A sensor/adaptor mechanism for enterovirus uncoating from structures of EV71. Nat Struct Mol Biol. 2012 19(4):424-9.

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FTE Category A staff submitted: 60.90

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